Benzopyrano pyridines

ABSTRACT

THIS INVENTION RELATES TO NOVEL COMPOSITIONS OF MATTER CLASSIFIED IN THE ART OF CHEMISTRY AS BENZOPYRANO PYRIDINE DERIVATIVES, TO PROCESSES FOR MAKING AND USING SUCH COMPOSITIONS AD BRONCHODILATOS AND TO THE INTERMEDIATES VALUABLE IN THE PREPARATION THEREOF.

United States Patent 3,803,153 BENZOPYRANO PYRIDINES Frank J. Villani,West Caldwell, N.J., assignor to Schering Corporation, Bloomfield, NJ.

No Drawing. Continuation-impart of application Ser. No. 90,004, Nov. 16,1970, which is a continuation-in-part of application Ser. No. 872,728,Oct. 30, 1969, which in turn is a continuation-in-part of applicationSer. No. 629,404, Apr. 10, 1967, all now abandoned. This applicationJan. 16, 1973, Ser. No. 324,024

Int. Cl. C07d 39/06 U.S. Cl. 260-29353 32 Claims ABSTRACT OF THEDISCLOSURE This invention relates to novel compositions of matterclassified in the art of chemistry as benzopyrano pyridine derivatives,to processes for making and using such compositions as bronchodilatorsand to the intermediates valuable in the preparation thereof.

This application is a continuation-in-part of my earlier filedapplication, Ser. No. 90,004, filed Nov. 16, 1970, now abandoned, whichin turn is a continuation-in-part of my earlier filed application, Ser.No. 872,728, filed Oct. 30, 1969, now abandoned, which in turn is acontinuationin-part of my earlier filed application, Ser. No. 629,404,filed on Apr. 10, 1967, now abandoned.

The invention sought to be patented in one of its composition of matteraspects is described as residing in the concept of a benzopyranopyridine, the tricyclic nucleus of which has the following structuralformula:

gt, Z

and the pharmaceutically acceptable acid addition salts thereof, whereinB, together with the. carbon atoms to which it is attached, represents afused pyridine ring, Q is a member of the group consisting of hydrogen,lower alkyl, halogen, lower alkoxy and hydroxy, Z is a member of thegroup consisting of and wherein A is a member of the group consisting ofpiperidyl, quinuclidyl and R: W is a member of the group consisting of Hand OH, and D is a member of the group consisting of piperidylidene,quinuclidylidene and R1 =YN\ R2 wherein R and R are members of the groupconsisting of hydrogen and lower alkyl and X and Y are respectivelysaturated lower aliphatic hydrocarbyl and hydrocarbylidene radicalscontaining two to four carbon atoms.

The novel compounds of Formula I are in essence final products, althoughas it will be described later, some of the final products have theadditional utility 3,803,153- Patented Apr. 9, 1974 I I10H-[11benzopyran0[3,2-b1pyridine-10 one 2 s 1 9 0 10 (I 4 5 6 0 3| 7 i8 10H-[1]benzopyrano[3,2-c]pyridine-10-one (III) 7 5H-[1] benzopyrano[2,3-c1pyridine-5-one i i 7 5H-[1]benzopyrano[2,3-b]pyridine5-oneAlthough the foregoing nomenclature is the approved method of naming thetricyclic nucleus of the compounds of this invention, the compounds willalso sometimes be hereinafter referred to as derivatives ofaza-xanthenes corresponding to the foregoing Formulae II, III, IV and V,all of which may be generically represented by the structural formula:

wherein B and Q are as previously described.

Embraced within the composition aspect of the concept represented byFormula VI are the l-aza, 2-aza, 3-aza and 4-aza xanthene 5-ones,corresponding to the compounds depicted in Formulae V, IV, HI and H,respectively. It is also apparent that the compounds of Formula I areamines attached to an aza-Xanthene nucleus at the 5-position thereofthrough a hydrocarbon connecting link Wherein at least two carbon atomsseparate the nitrogen atom from the 5-position carbon atom of thetricyclic nucleus. By Way of furher definition, those compounds fallingwithin Formula I wherein W represents hydroxy, are sometimes referred toas carbinols, those wherein W represents H are sometimes referred to assaturated compounds and those having a doubly bound substituent D, aresometimes referred to as unsaturated compounds or alkylidene compounds.

The substituent A, as described herein includes a limited number ofamino substituents exemplified by 3-piperidyl, 4-piperidyl, N-loweralkyl (preferably methyl) 3- and 4- piperidyl, N-trifluoroethyl-3- and4-piperidyl, and 3-quinuclidyl. Included within the definition of A isthe group with X being defined as a hydrocarbyl group having 2 to 4carbon atoms exemplified by ethyl, propyl and isobutyl. The

moiety is defined as amino, lower alkylamino (preferably methyl amino)and di-lower alkyl amino (preferably dimethyl amino). Representative ofthe D moiety are those radicals defined for A but being attached to the5-position carbon atom of the tricyclic nucleus through a double bond.Representative of the D moiety are such radicals as 3-piperidylidene,4-piperidylidene, N-methyl 3 piperidylidene, N-methyl-4-piperidylidene,3-quinuclidylidene, N-trifluoroethyl-4 piperidylidene, N trifluoroethyl3- piperidylidene, dimethylaminopropylidene, methylaminopropylidene,dimethylaminoethylidene, and dimethylamino-Z-methylpropylidene.

Representative of the Q substituents in the benzenoid moiety of thetricyclic nucleus are halogeno (preferably chloro and bromo), loweralkyl (preferably methyl), lower alkoxy (preferably methoxy) andhydroxy.

Preferably the substituents are located in the 7- and/or 8-positions ofthe aza-xanthene nucleus.

The compounds contemplated as falling within Formula I are basic incharacter and form acid addition salts with acids. These salts sometimesincrease solubility and lend themselves better to formulation than dothe free bases. Accordingly, the pharmaceutically acceptable acidaddition salts of the free bases are contemplated as being within theconcept in its composition aspect. Such salts include those derived frommaleic, salicylic, succinic, methyl sulfonic, tartaric, citric,hydrochloric, hydrobromic, sulfuric, phosphoric and the like.

In one of its process aspects, the invention sought to be patentedresides in the concept of producing a compound of Formula I by reactinga 5 keto-aza-xanthene with an organometallic compound bearing an aminosubstituted group embraced by the substituent A and hydrolyzing thecomplex thereby formed. The organometallic reactant may be a Grignardtype reagent such as N-methyl-4- piperidyl magnesium halide, preferablychloride or bromide. This step may be summarized by the followingreaction sequence:

0 O AM h 11 If Q B l/O,

benzyl or carboethoxy groupings. The carbinol so formed will accordinglycontain the blocking group which is easily cleaved by catalytichydrogenation and/or hydrolysis to regenerate the corresponding mine.

In a preferred procedure, a S-keto-aza-xanthene (VI) is added either insolid form or in solution in an inert solvent to a Grignard reagentcontaining the substituent A which is also in an inert solvent such as,for example, ether, benzene, tetrahydrofuran and the like.Representative of the organometallic reactant are N methyl 4- piperidylmagnesium chloride, dimethylaminopropyl magnesium chloride, and the likewhich are prepared in a known manner from magnesium and thecorresponding amino alkyl halide. The reaction mixture may be heated,preferably under reflux, after which time it is subjected to hydrolysis.Hydrolysis under practically neutral conditions such as is effected byammonium chloride results in formation of the carbinol (VII) which isisolated from the reaction mixture by extraction with a water-immisciblesolvent such as ether, chlorinated hydrocarbons and the like. Thecarbinols of Formula I, may be utilized as such or in the form of theiracid addition salts.

The carbinols are valuable intermediates in the production of theunsaturated compounds of Formula I, that is those compounds wherein Zrepresents C=D. The carbinols are relatively easily dehydrated toproduce an exocyclic unsaturated compound of Formula I. The dehydrationmay be eifected by heating the carbinol with known dehydrating agentssuch as alcoholic hydrogen chloride, phosphorous oxychloride, phosphoricacids such as polyphosphoric acid, sulfuric acid, zinc chloride, alkalipyrosulfate and other similarly acting agents. These unsaturatedproducts (wherein Z of Formula I represents C=#D) may be isolated asfree bases or in the form of their acid addition salts. Thus, thedehydration of the carbinols to produce the corresponding unsaturatedanalog represents a further aspect of the process concept of theinvention sought to be patented.

A further utility of the exocyclically unsaturated compounds describedabove is that wherein they serve as mtermediates in the preparation ofthe saturated compounds of Formula I (wherein Z represents Thesesaturated compounds are prepared by catalytic hydrogenation of thedouble bond preferably with palladium and hydrogen.

The saturated compounds of Formula I (wherein A represents are alsopreparable by direct alkylation of an aza-xanthene according to thefollowing reaction scheme:

A-Cl 3 basic condensing agents Q.

H H A I) (VIII) In the foregoing reaction scheme, the substituents A, B,and Q have the same meaning as described heretofore. This reactionconstitutes the condensation of an organic halide (preferably chlorideor bromide) bearing the substituent A, with an appropriate aza-xanthene.The reaction is carried out in an inert solvent such as ether, tolueneor xylene, preferably at reflux temperature, and in the presence of acondensing agent such as sodamide or potassium amide. Representative ofthe halides which may be used in this reaction are dimethylaminopropylchloride, dimethylaminoethyl chloride and the like. The

5 reaction product is obtained by neutralization of the mixture withmineral acid, followed by treatment with aqueous alkali and extractionwith a water immiscible solvent.

A method of preparing the unsaturated compound analogs wherein thesubstituent A or D has only two carbon atoms separating the amino moietyfrom the 5-position of the tricyclic nucleus is that which firstinvolves the condensation of a S-keto-aza-xanthene (VI) with abromoacetic ester (preferably ethyl bromoacetate) in the presence ofzinc, the well known Reformatsky condensation, which gives rise to acarbethoxy intermediate IX:

In the foregoing reaction, B and Q have the same significance asascribed heretofore. The reaction is effected in an inert solvent suchas refluxing toluene or xylene and the product, IX, separated therefromaccording to methods well known in the art. The ester, IX, is thensubjected to dehydration such as by heating with thionyl chloride toafiord the exocyclically unsaturated analog, X, which is saponified bytreatment with acid or alkali to yield the carboxylic acid, XI. Thecarboxylic acid, XI, is converted into an amide, XII, by first formingthe acid chloride by means of thionyl chloride followed by reaction withthe amine HNR R This sequence of reactiOns is depicted in the followingscheme and for convenience only the 5-position of the tricyclic systemis shown.

\ dehydration r HO CHaCOOCaHs fi saponification CH 0 O C2Hs C i S 0 C120 II CHCOOH flHNRlRfl HCONRiR:

(XI) (XII) In this reaction sequence, NR R has the same significance asascribed heretofore but is preferably a tertiary amino group. Selectivereduction of the amide group by means of lithium aluminum hydride, forexample, yields the amino alkylidene, XHI, which may be furthersaturated to yield the aminoalkyl, XIV, by catalytic hydrogenation withpalladium.

LlAlHl o Pd 0 CH-CHiNRtRI H2 H omornNmR,

(XIII) (XIV) Compounds XIII and XIV are representative of those ofFormula I having two carbons separating the amino group --NR R from the-position of the tricyclic nucleus.

A further approach to the preparation of the alkylidene compounds ofthis invention is that whereby essentially all groups are present (i.e.the A substituent is attached) except for the bonding of the 5-positionto the benzenoid ring. For example, reacting 3-phenoxy-2-cyanopyridinewith N-methyl-4-piperidylidene magnesium chloride forms the intermediateketone which upon cyclic dehydration with polyphosphoric acid to formthe desired 6 exocyclically unsaturated compounds. Quite obviously thiscyclic dehydration goes thru an imino intermediate (e.g.

wherein A and D are as previously defined) and thus the cyclicdehydration of either and/or the keto or imino intermediates areincluded.

In addition to the foregoing methods of preparation for the compounds ofthis invention the unsaturated compounds of this invention mayalternatively be prepared by the following sequence of reactions whichfor the sake of convenience show only the 5-position of the tricyclicsystem:

The S-keto intermediates of Formula VI are prepared by a variety ofprocedures of which I prefer an intramolecular cyclization of a phenoxypyridine carboxylic acid according to the following scheme:

(xv) (IV) wherein the B and Q designations are as hereinabove defined.The cyclization of the phenoxy pyridine carboxylic acid (XV) ispreferably effected by heating the acid with polyphosphoric acid in thetemperature range of about to C. whereby the cyclization occursresulting in the formation of the ketone. Quite apparently, the choiceof the phenoxy pyridine carboxylic acid will determine the particularisomer produced. Alternatively, the cyclization may advantageously beeffected (e.g. in the preparation of7-chloro-l0H[1]benzopyrano[3,2-b]-pyridine-IO-one from3-(3-chlorophenoxy)picolinic acid so as to insure the minimization ofthe formation of 9-chloro- 10H[l]benzopyrano[3,2-bJ-pyridine-10-one) byan intramolecular Friedel-Crafts reaction. By this method the carboxylicacid is first converted to its acid chloride such as by means of thionylchloride (or phosphorous trichloride or oxalyl chloride for example)followed by treatment with aluminum chloride, whereby cyclizationoccurs. The cyclization is carried out according to standard techniquesfor effecting a Friedel-Crafts reaction, namely heating the mixture inaninert solvent such as carbon disulfide, petroleum ether, benzeneand thelike and isolating the cyclized product therefrom.

The 4-aza rketones of Formula II are preferably prepared by thefollowing sequence of reactions:

wherein Q is as previously defined.

OAR: N

(XXI) (XXII) (XXIII) i-ooon H Q Q being as previously defined.

The preparation of the 2-aza ketones is effected by the followingreaction sequence:

OH B Etc 03 N V Q K/J Q CH: C

(XXIV) a (xxv (XVI) xxvrr /KMI10 r/ PPA N W K/ Q coon xxvrrr Thepreparation of the l-aza ketones is efiected by heating 2-chloronicotinic acid with an appropriate Q-substituted phenol and cyclizingthe 2-pl1enoxy nicotinic acid by heating with polyphosphoric acid, or byherein described alternative cyclization with aluminum chloride.

The preparation of aza-xanthenes, i.e., those compounds of Formula VIwherein the S-keto group is reduced to a methylene (0H moiety, isaccomplished by first chemically reducing the S-keto moiety to thecorresponding carbinol which in turn, is reduced to the methylene. Thiscan be effected with sodium borohydride, with zinc dust in ammonia, orby catalytic reduction using platinum oxide or Raney nickel. Thecarbinols may be converted to the methylene by chlorinating with thionylchloride and then replacing the chlorine atom with hydrogen by refluxingthe chloro intermediate in the presence of a mixture containing zincdust, potassium iodide and acetic acid.

PREPARATION A.--4-AZA-XANTHENE-5-ONES Example I 10H[ 1]benzopyrano[2,3-b]pyridine-10-one Step I.Dissolve 56.7 g. of metachlorperbenzoic acid in 750 ml. of dry chloroform. Add a solutioncontaining 51.3 g. of 3-phenoxypyridine in ml. of chloroform and allowthe resulting mixture to stir at room temperature for 20-24 hrs. Washthe reaction mixture with consecutive washings using 20% aqueouspotassium iodide, 20% sodium thiosulfate, 20% sodium hydroxide solutionand water. Concentrate the washed reaction mixture on a steam bath andtriturate with petroleum ether. Recrystallize the product frombenzene/petroleum ether (50:50) to yield 3-phenoxypyridine-N-oxide, M.P.78-80 C.

Step II.-In a round bottom flask, melt 43 g. of the N-oxide of Step I at80-85 C. and, in a dropwise fashion, maintaining the temperature of80-85 C., add 29 g. of dimethyl sulfate over a period of 1-2 hours. Heatthe resulting mixture on a steam bath for two hours. Cool and dissolvethe product in 70 ml. of water, maintaining the water solution in thetemperature range of 0-10 C. Bubble nitrogen gas over a freshly preparedsolution of sodium cyanide (33.8 g.) for one hour, keeping the solutionat 0-5 C. Add the N-oxide product to the sodium cyanide solution,maintaining the temperature at 05 C. during the addition (2-3 hrs.) andallow the resulting mixture to come to room temperature, stirring themixture for 10 hours under a blanket of nitrogen gas. Extract thereaction mixture with chloroform and water-wash the extract.

Remove the chloroform by evaporation and recrystallize the product frombenzene hexane to yield the desired 2-cyano-3-phenoxypyridine, M.P. 7576C.

Step III.Heat a mixture of 34.5 g. of the 2-cyano-3- phenoxypyridine and1380 g. of polyphosphoric acid at 195-200 C. for 4-6 hours. Cool thereaction mixture, pour into ice and basify with sodium hydroxide.Extract the product with chloroform, water wash the chloroform extract,evaporate oil the chloroform and recrystallize the residue from benzenepetroleum ether to yield the desired 10H[1]benzopyrano [3,2-b] pyridine1O one, M.P. 204- 205" C.

Step IV.-At reflux temperatures, heat a mixture containing 25 g. of the2-cyano-3-phenoxypyridine, 25 g. of potassium hydroxide, 200 ml. waterand 500 ml. of ethanol for 20-26 hours. Concentrate in vacuo anddissolve the residue in a minimal amount of water. Acidity with aceticacid, filter and air dry the resulting 3-phenoxy picolinic acid.

Step V.Suspend 10.8 g. of the 3-phenoxy picolinic acid in ml. of drybenzene and add at 10-15 C. 10 ml. of thionyl chloride. Heat thereaction mixture on a steam bath for 2 hours, remove the solvents invacuo, add 350 ml. of carbon disulfide and with vigorous stirring, add13 g. of anhydrous aluminum chloride and allow the reaction mixture tostir for 19 hours. Remove the excess carbon disulfide add 500 ml. ofwater and 100 ml. of concentrated hydrochloric acid to the residue.Extract this solution with chloroform and discard the chloroformextracts. Basify the aqueous solution with sodium hydroxide. Extract thedesired product With chloroform. Evaporate oh. the chloroform andrecrystallize the desired product from benzene petroleum ether to yield10H[l]- benzopyrano[2,3-b1pyridine-l0-one, M.P. 204-205 C.

Example II 7-chloro-1OH[ 11benzopyrano 3,2-b] pyridine- 1 O-one Heat at-200 C. for 4 hours, a mixture containing 31.6 g. of 3-bromo pyridine,51.2 g. of m-chloro phenol,

g. of copper powder and 55.2 g. of anhydrous potassium carbonate.Dissolve the resulting mixture in water making strongly basic withsodium hydroxide and steam distil the resulting mixture. Extract thesteam distillate with several portions of ether. By following theteachings of Steps II, IV, and V of Example I, there is produced 7-chloro-H[1]benzopyrano[3,2-b]pyridine-10-one.

PREPARATION B.-3-AZA XANTHENE-S-ONES Example III10H[1]benzopyrano[3,2-c]pyridine-10-one Step I.Stir on a steam bath for4 hours a mixture containing 30.8 g. of 4-nitro-3-picoline-N-oxide, 37.6g. of phenol and 27.6 g. of potassium carbonate. Dissolve the resultingmixture in water and make strongly basic with sodium hydroxide. Extractthe product with chloroform, evaporate off the chloroform andrecrystallize the residue from benzene petroleum ether to yield4-phenoxy-3- picoline-N-oxide, M.P. 113-116 C.

Step II.Dissolve g. of the N-oxide prepared in Step I in 250 ml. ofchloroform and cool the solution to 05 C. To the cooled solution add, ina dropwise fashion, with constant stirring, a solution of 30.8 g. ofphosphorous trichloride in 50 ml. of chloroform. After completion of theaddition of phosphorous'trichloride, reflux the mixture for 3 hours,cool to room temperature and pour into a large volume of ice water.Basify the mixture with sodium hydroxide and extract with severalportions of chloroform. Distil off the chloroform and distil the residueto yield 4-phenoxy-3-picoline, B.P. 104- 107 C./0.4 mm.

Step III.Suspend 35 g. of 4-phenoxy-3-picoline in 41. of water and heatthe suspension to 70-80 C. Add in several small portions over a periodof 6 hours, 90 g. of potassium permanganate. Stir and heat the mixturefor 12 hours at 70-80 C. Filter the resulting mixture, wash the filtercake with hot water and concentrate the filtrate to approximately800-900 ml. Acidify the filtrate with acidic acid. Add a saturated watersolution of copper sulfate until the precipitation of the copper salt iscomplete. Filter the copper salt, water wash and suspend the salt in hotwater. Saturate the solution with hydrogen sulfide. Filter off thecopper sulfide and concentrate the filtrate to dryness. Recrystallizethe residue from ethanol to yield 4-phenoxy nicotinic acid, M.P. 133-l35C.

Step IV.--Heat g. of 4-phenoxy nicotinic acid with 800 g. ofpolyphosphoric acid for 4-6 hours at 140145 C. Pour the resultingmixture into ice water and basify with sodium hydroxide. Extract thesolution with chloroform and evaporate off the chloroform to obtain aresidue which is triturated with petroleum ether and recrystallize fromisopropyl ether to yield 10H[1]benzopyrano[3,2-c1pyridine-10-one, M.P.190-191 C.

PREPARATION C.--2-AZA-XANTH-ENE-5-ONES Example IV5H[1]benzopyrano[2,3-c]pyridine-S-one Step I.Heat at 230-250 C., amixture containing 65.4 g. of 3-hydroxy-4-picoline, 78.5 g. ofbromobenzene, 82.8 g. of potassium carbonate and 6 g. of copper powderfor 3 hours. Pour the resulting mixture into water and make stronglybasic with sodium hydroxide and steam distil the resulting mixture tocollect about 8 l. of distillate. Saturate the distillate with salt andextract with ether. Dry the ether extract (sodium chloride) and distilto obtain 4-methyl-3-phenoxypyridine, B.P. 133- 135 C./l0 mm.

Step 11.4uspend 40 g. of 4-methyl-3-phenoxy pyridine, 4 l. of water andwarm the resulting suspenison to 70 on a steam bath. Add, in severalportions, 79 g. of potassium permanganate and stir the resulting mixture10 for 2 0 hoursat 70 C. Filter the resulting mixture, wash the filtercake with hot water and concentrate the filtrates to approximately /2the volume. Acidify the concentrated filtrate with acetic acid. Filterand recrystallize the 3-phenoxy isonicotinic acid from dilute ethanol,M.P. 235-237 C.

Step III.Using the product of Step II, follow the procedure ofPreparation B, Step III, to effect cyclization to obtain5H['1]benzopyrano [2,3-c]pyridine-5-one, M.P. 157-158 c.

PREPARATION D.-1-AZA-XANTHENE-5 -ON ES Example V5H[1]benzopyrano[2,3-b1pyridine-5-one Dissolve g. of sodium methoxide in700 ml. of methanol, add 440 g. phenol and 157 g. of 2-chloronicotinicacid. Evaporate off the methanol solvent and heat the residue at -190 C.for 1 hour. Pour the resulting mixture into ice water and acidity themixture with acetic acid to produce 2-phenoxy nicotinic acid, M.P. 172-180 C.

Step II.Heat 168.3 g. of Z-phenoxy nicotinic acid with 6000 g. ofpolyphosphoric acid at 120 C. for 5 hours and pour the resulting mixtureinto water. Basify with sodium hydroxide and filter off the ketone.Water wash thoroughly until the extracts are no longer basic. Air drythe desired 5H[1]benzopyrano[2,3-b]pyridine-5- one, which isrecrystallized from benzene or ethanol to yield the product with a M.P.of 178182 C.

The foregoing preparations set forth methods for synthesizingintermediates in the preparation of final compounds of Formula I. Withthe exception of Example II, these preparations give rise to anaza-xanthene-S-one, unsubstituted in the benzenoid ring. As previouslystated, to prepare the ketones having substituents at one or more of the6-, 7-, 8- and 9-positions, one merely employs the appropriatelyQ-substituted reactant. If these reactants are substituted the Qsubstituent will appear in the benzeneoid moiety of the aza-xanthene,the position being dependent upon the position in the initial reactant.Thus, the initial reactant may bear an ortho, meta, or para substitutedchloro,.bromo, hydroxy or methoxy (or a protecting group which is latercleaved to the free hydroxyl which is then converted to a methoxyradical). In those instances wherein the Q-substituted reactants giverise to isomers upon cyclization, it is preferred to separate suchisomers by column chromatography whereby the mixture is absorbed onalumina and eluted with benzene/hexane fractions containing varyingproportions of solvent. Combination of like eluates as determined byinfra-red, ultra-violet and thin layer chromatographic techniques,provides for separation and isolation of the respective isomers. TheQ-substituted aza-xanthenes reactants may be prepared from techniqueswell known to one of ordinary skill in the art. Representative of suchQ-substituted ketones are:

7-chloro-10H[ 1]benzopyrano [3,2-b]pyridine-10-one; 7-bromo-10H[1]benzopyrano[3,2-b]pyridine-1-0-one; 7-methoxyl-0H[ 1 benzopyrano[3,2-b pyridine- 1 0-one; 7,8-d1methoxy-10H[ 1]-benzopyrano[3,2-b]pyridine-10- one; I 8-chloro-10H[ 1]benzopyrano[3,2-b]pyriidne-10-one; 7-chloro-10H[1Jbenzopyrano[3,2-c]pyridine-10-one; 7-bromo-10H1]benzopyrano[3,2-c]pyridine-10-one; 7-methoxy-10H[ 1 benzopyrano[3,2-c]pyridine-10-one; 7, 8-dimethoxy-10-H[ 1 benzopyrano[3,2-c]pyridine-10- one; 7,8-dihydroxy-10H[l]benzopyrano[3,2-c]pyridine-10- one; 8-chloro-10H[ l ]benzopyrano [3,2-b] pyridine- 10-one; 8-chloro-10H[ l ]benzopyrano[3,2-c]pyridine10-one;

8-chloro-5H[ 1]benzopyrano [2,3-c] pyridineone;

8 -bromo-5H[ l1benzopyrano [2,3-c] pyridine-S-one; 8-methoxy-5H[ lbenzopyrano [2, 3-c] pyridine-S-one; 7,8-dimethoxy-5H[ 1 benzopyrano[2,3-c] pyridine-S-one; 7,8-dihydroxy-5H[ l benzopyrano 2,3-c]pyridine-S-one; 8-chloro-5 H 1 benzopyrano [2,3 -b pyridino-S-one;8-bromo-5H[ l ]benzopyrano [2,3-b1pyridine-5-one; 8-methoxy-5H[ 1benzopyrano [2, 3-b pyridine-S-one; 7,8-dimethoxy-5H[ 1] benzopyrano[2,3-b1pyridine-5-one; 7,8-dihydroxy-5H[ l]benzopyrano [2,3-b]pyridine-S-one;

and 7-chloro-5H[ 1]benzopyran0 [2,3 -b] pyridine-S-one;

respectively.

PREPARATION OF CARBINOLS Example VI 5-hydroxy-5- (N-methyl-4-piperidyl)SH 1 benzopyrano [2,3-b]pyridine Dissolve 5 g. of sodium metal in about500 ml. of anhydrous liquid ammonia and add a suspension containing 19.7g. of 5H[1]benzopyrano[2,3-b]pyridine-5-one in 250 ml. of anhydroustetrahydrofuran. Stir the resulting mixture for 25-30 min. and add asolution containing 13.3 g. of freshly distilledN-methyl-4-chloropiperidine in 20 m1. of tetrahydrofuran. Stir thereaction mixture for 4-6 hours and allow the mixture to stand for anadditional 14 hours. Add liquid ammonia and 20 g. of ammonia chloride.Decompose the reaction mixture by the dropwise addition of about 100 ml.of water and extract the mixture with chloroform. Water-wash andevaporate the chloroform solvent and triturate the residue frompetroleum ether. Recrystallize the product from benzene petroleum ethermixture to yield the carbinol of this example, M.P. 208-210 C.

Example VH 7 -chloro-5 -hydroxy-5 (N-methyl-4-piperidylidene) 5 H[ 1 1benzopyrano [2, 3-1:] pyridine Prepare the Grignard reagent from 7.2 g.of magnesium metal and 48.9 g. of N-methyl-4-chloro-piperidine in 300ml. of tetrahydrofuran and employing a crystal of iodine and 1 cc. ofethylene dibromide as a catalyst, reflux the mixture until the magnesiummetal is consumed (2-3 hours) and cool the mixture to room temperature.Add a suspension of 21.5 g. of 5H-[1]benzopyrano[2,3-b]pyridine-S-one in200 m1. of tetrahydrofuran and stir the resulting mixture for 6-8 hoursat room temperature. Decompose the reaction with ammonium chloridesolution (10%) and extract with chloroform. Concentrate to a residue andrecrystallize from ether to obtain the carbinol of this example, M.P.181-185 C.

PREPARATION OF UNSATURATED COMPOUNDS BY DEI-LYDRATION OF CARBINOLSExample VIII 5- (N -methylyi-4-piperidylidene) -5 H 1] benzopyrano[2,3-'b pyridine Heat on a steam bath for 20-24 hours a mixturecontaining 10 g. of the carbine! of Example VI and 400 g. ofpolyphosphoric acid. Pour the mixture into ice water and make alkalinewith sodium hydroxide. Extract with chloroform. Water wash thechloroform extract and concentrate to a residue. Recrystallize theresidue from acetonitrile and ethyl acetate to yield5-(N-methyl-4-piperidylidene)-5H[ l benz0pyrano[2,3-b] pyridine, M.P.125- 217 C.

12 Example 1X 5- (N-methyl-4-piperidylidene)-5H[ lbenzopyrano[2,3-b]pyridine Stir at room temperature a mixture of 10 g.of the carbinol of Example VI with 2100 ml. of sulfuric acid for 2hours. Pour the resulting mixture into ice and neutralize with sodiumhydroxide. Extract with chloroform, water wash and concentrate thechloroform extract to a residue. Recrystallize the product fromacetonitrile and ethyl acetate.

Example X 5 (N-trifluoroethyl-4-piperidylidene) 5 H 1 ]benzopyrano-[2,3-b]pyridine hydrochloride To a solution containing 21.2 g. ofcyanogenbromide in ml. of benzene add a solution containing 59.6 g. of5(N methyl 4 piperidylidene) 5H[11benzopyrano- [2,3-b1pyridine in 3 l.of acetone. Allow the solution to stir overnight at room temperature.Filter and concentrate the filtrate to a residue. Add petroleum ether tothe residue, filter the product and recrystallize the product fromethanol water. Dissolve the N-cyano intermediate in a mixture containing60 ml. of hydrochloric acid and 600 ml. of acetic acid and 400 ml. ofwater and reflux the resulting mixture with stirring for 20 hours.Concentrate the resulting solution to dryness. Neutralize With ammoniumhydroxide and extract with chloroform. Eyaporate 01f the chloroform andrecrystallize the residue from hexane to yield5(4-piperidylidene)5I-I[l]benzopyrano[2,3-b]pyridine. Prepare a solutioncontaining 13.2 g. of 5(4-piperidylidene)5H[1]benzopyrano[2,3-b]pyridine in ml. of xylene and add 6 g. of trifluoroethyltrichloromethane sulfonate and reflux the resulting mixture for 15hours. Cool and filter the reaction mixture and evaporate the xylene.Extract the residue several times with refluxing petroleum ether.Concentrate the petroleum ether extracts to incipient recrystallization.Recrystallize from hexane, M.P. 123-125 C.

Thus, by the employment of the appropriate starting reactants and byfollowing the procedures of the foregoing examples, there is produced:

10( N-methyl-3 -piperidylidene) 1 OH l benzopyrano [3 ,2-b] pyridine;

10 (N-methy1-3-piperidylidene) 10H[ 1 benzopyrano [3 ,2b] pyridine;

10(3-quinuclidylidene)-1OH[ l ]benzopyrano [3 ,2-b]

pyridine;

1 0 N-trifluoroethyl-4-piperidylidene 1 0H[ 1 benzopyrano[ 3 ,2-b]pyridine;

10 (N-trifluoroethyl-3 -pip eridylidene) -10H[ 1] benzopyrano [3 ,2-b]pyridine;

l0( 3-dimethylaminopropylidene) 1 0H[ 1 benzopyrano [3 ,Z-b] pyridine;

10 3-dimethylamino-2-methylpropy1idene) 10H[ 1 benzopyrano [3,2-b]pyridine;

10 (S-methylaminopropylidene) -1OH[ 1]benzopyrano [3 ,2-b] pyridine;

10(dimethylaminoethylidene) -lOH[ l benzopyrano [3 ,Z-b] pyridine;

1 (l N-methyl-4-piperidylidene) 10H[ 1 benzopyrano [3 ,2-c] pyridine;

10 (N-methyl-3 -piperidylidene) 10H[ 1]benzopyrano [3 ,2-c] pyridine;

1 0'( N-methyl-3-quinuclidylidene) 1 0H[ 1]benzopyrano [3,2-0] pyridine;

10(N-trifluoroethyl-4-piperidylidene)-1OH[ 1] benzopyrano [3,2-c]pyridine;

10(N-trifluoroethyl-3-piperidylidene)-10H[ 1] benzop yrano 3 ,2-c]pyridine;

10( 3 -dimethylaminopropylidene)-10H[ l benzopyrano [3,2-0] pyridine;

13 10 3 -dimethylamino-Z-methylpropylidene).10H[ 1] benzopyrano 3,2-c]pyridine;

' 10(3-methylaminopropylidene)-10H[1]benzopyrano-.

N-methyl-4-piperidylidene) -5 H 1 benzopyrano [2,3-c] pyridine;

5- (N-methyl-3-piperidylidene -5 H 1] benzopyrano [2,3-c]pyridine;

5(3-quinuclidylideue)5H[1]benzopyrano[2,3-c]

pyridine;

5 (N-trifiuoro ethyl-4-piperidylidene) S'H 1]benzopyrano [2,3-c]pyridine;

5 (N-trifluoroethyl-S-piperidylidene) 5 H 1]benzopyrano 53-dimethylaminopropylidene 5 H 1]benzopyrano [2,3-c1pyridine;

5 (dimethylamino-a-methyl-propylidene) 5H 1 benzopyrano [2,3-c]pyridine;

5 3-methylaminopropylidene) 5H[ 1 benzopyrano [2,3-c] pyridine;

5- (dimethylaminoethylidene 5H[ 1]benzopyrano [2,3 c] pyridine;

5 (N-methyl-4-piperidylidene) 5 H 1 lbenzopyrano [2,3-b] pyridine;

5 N-methyl-3 -pip eridylidene 5H[ 1]benzopyrano [2,3-b pyridine;

5 3-quinuclidylidene 5 H l benzopyrano [2,3-b pyridine;

5 (N-trifluoroethyl-4-piperidylidene) 5H[ 1 benzopyrano [2,3-b]pyridine;

5 N-trifluoro ethyl-3-pip eridylidene) 5 H 1]benzopyrano [2,3-b]pyridine;

5 (3 -dimethylaminopropylidene 5 H 1 lbenzopyrano [2,3-b] pyridine;

5 (3-dimethylaminopropylidene)5H[1 benzopyrano [2,3-b1PYridine;

5 (dimethylamino-u-methyl-propylidene) 5H[1] [2,3-b] pyridine; V

5 (3 -methylaminopropylidene) 5H[ 1]benzopyrano [2,3-b1pyridine;

5 (dimethylaminoethylidene) 5H[ 1 benzopyrano [2, 3-b] pyridine and theS-chloro, 8-bromo, 8-methoxy, 7,8-dimethoxy, 7,8-dihydroxy, 7-chloro,8-hydroxy and other Q-substituted analogs of each of the foregoing, saidcompounds also being amenable to hydrogenation procedures of theexamples described hereinbelow to produce the saturated analog thereof.

PREPARATION OF SATURATED COMPOUNDS Example XI 5 (N-methyl-4-piperidyl)5H 1 benzopyrano [2,3 -b] pyridine Hydrogenate in a Parr shaker asolution of 6.8 of 5- (N methyl 4 piperidylidene)5H[l]benzopyrano[2,3-bJpyridine in 100 ml. of ethanol in the presence of 0.5 g. of platinumoxide under 50 lbs. pressure of hydrogen until an equivalent quantity ofhydrogen is absorbed. Filter and concentrate the filtrate to a residueand recrystallize the residue from petroleum ether.

PREPARATION OF ACID ADDITION SALTS Example XII 5(N-methyl-4-piperidylidene) 5H 1]benzopyrano [2,3-b1pyridine maleateDissolve 13.9 g. of 5(N-methyl-4-piperidylidene)5H-[1]benzopyrano[2,3-b]pyridine in 50 ml. of ethyl acetate.

14 Add a solution of 5.8 g. of maleic acid in 100 ml. or refluxingethylacetate and reflux for 10 min. Allow to cool, filter andrecrystalliz/e from ethanol ether to yield 5(N- methyl 4piperidylidene)5H[1]benzopyrano[2,3 b] pyridine maleate, M.P. 204206 C.

Example XHI 5 -quinnclidylidene-5 H 1 benzopyrano [2,3-1 pyridine StepI.Dissolve 8.7 g. of sodium metal in 1 l. of anhydrous ammonia. Withvigorous stirring add a dropwise solution of 32.6 g. of5H[l]benzopyrano[2,3-b]pyridine- 5-one in about 600 ml. drytetrahydrofuran and stir for an additional 0.5 hr. Then add a solutionof 24 g. of 3- chloroquinuclidene in 30 ml. of tetrahydrofuran and stirovernight. Add 30 g. of solid ammonium chloride, allow the. excessammonia to evaporate and cautiously add about 200 ml. of Water andremove the tetrahydrofuran by distillation in vacuo. Extract the productwith chloroform, wash the chloroform extracts with water and concentrateto a residue. The product, after recrystallization from ethanol, yieldsS-OH-S (3-quinuclidene)5H-[1]- benzopyrano[2,3-b1pyridine maleate, M.P.248250 C. Step II.-Prepare a solution of 24 g. of oarbinol from Step I,21 g. of p-toluenesulfonic acid and 600 ml. of acetic anhydride. Heatthis solution for 5 hrs. on a steam bath, pour into ice water, andbasify with sodium hydroxide. Filter the product and recrystallize fromchloroform-hexane to give the produce of this example having a M.P. of198-200 C.

Step III.Dissolve 5 g. of the quinuclidylidene derivative from Step IIin 200' ml. of anhydrous ether and add a saturated solution of hydrogenchloride gas in ethanol until precipitation is complete. Filter theproduct and recrystallize from ethanol to yield 5-(3-quinuclidylidene)5H 1 -benzopyrano [2,3-b] pyridine hydrochloride, M.P. 312314 C.

Having described the preparation of the compounds of this invention, theprocess by which these compounds may be used as therapeutic agents willbe described.

The compounds of this invention possess the inherent applied-usecharacteristic of relaxing the bronchial muscle. Thus, the compounds ofthis invention may be characterized as bronchodilators useful in thetreatment of pulmonary disorders characterized by broncho-congestionand/or broncho-constriction, such as bronchitis, emphysema, bronchialasthma, pulmonary edema and pneumocomosis.

It has also been found from the results of a modified histamine-aerosoltest (designed to measure the effect of medicaments on the time-of-onsetof histamine induced dyspnea) that the compounds of this inventiongreatly increase the time required to induce dyspnea in animals (e.g.guinea pig). This test is collaterally a measure of the medicamentsability to dilate the bronchial muscle in vivo and may be used forside-by-side comparison with commercially available bronchodilators. Inother words, the compound actually causes a dilatation of the bronchialmuscle rather than only counteracting the effects of the histaminepresent.

In addition to the foregoing assay methods it is also found that thecompounds are effective in the anti-IgE screen (PCA) (see Journal ofParasitology, vol. 53, p. 752, 1967). The compounds of this inventionhave been found to be more effective in this assay (e.g. at 0.2-2.5 mg./kg. of body weight) for the prevention of the release of histamine thanother prior art anti-histamines even though these prior artanti-histamines are known to have a greater potency in clinicalanti-histamine assays. This suggests that the mechanism of action of thecompounds of this invention is indeed unique. Indeed, according toanother assay technique (see Journal of Immunology, vol. 100, p. 622,1968), it is found that the compounds of this invention exhibitinhibition of histamine release 15 from isolated rat peritoneal mastcells. The preferred compounds of this invention block histamine releaseaccording to the foregoing assay at 10* to 10* molar concentrations.

In practice, based upon standard pharmacological animal studies,particularly in the guinea pig, it has been found that oraladministration 0.1-5 rug/kg. of animal body weight per dose will elicitthe desired bronchodilating effect, that said dose may be administredfrom 1-4 times per day.

Of course, in all instances the optimium daily oral dose level useful inthe control of the pulmonary disorder will vary depending upon thepotency of the specific compound, the severity of the condition beingtreated, as well as the reaction sensitivity of the animal host beingtreated.

As is true for most classes of therapeutically useful compounds, certainsub-classes and certain specific compounds are found to be moreeifective than other members of the general class. Of the compounds ofthis invention amino alkylidene derivatives, i.e. those compoundsdesignated by O=D of Formula I are preferred bronchodil'ators.Especially preferred compounds are those derivatives bearingN-methyl-4piperidylidene, dimethylarninopropylidene,dimethylaminomethylidene, N trifluoroethyl-4-piperidylidene and3-quinuclidylidene substituents in the 5-position of the aza-xanthenenucleus. Preferred aza-xanthenes are the l-aza isomers of Formula I(i.e. those 5H[1]benzopyrano]2,3-b1pyridines having the foregoingaminoalkylidene substituents. Of particular therapeutic interest is5(N-rnethyl-4-piperidylidene)-5H [1]benzopyrano[2,3-b] pyridine becauseof its direct action upon the bronchi and thus such compound isespecially suitable for oral application for its direct bronchodilatingeffects. Other compounds of particular interest for theirbronchodilating effect are 5(3-quinuclidylidene)5H[1]benzopyrano[2,3-b1pyridine, 7 chloro-5(N-methyl 4 piperidylidene)5H[1]benzopyrano[2,3 b] pyridine, 8-chloro-5(N-methyl-4-piperidylidene) 5H 1 benzopyrano[2,3 b] pyridine,5-N-trifluoroethy1-4-piperidylidene) 5H[ 1 benzopyrano [2,3-b] pyridine.

In addition to their use as bronchodilating agents, the compounds ofthis invention also exhibit useful CNS effects. For example, in theisolation-induced aggression in mice assay technique (C. Y. Yen, R. L.Stonger and N. Millrnan, Archives International Pharmacodynamie, vol.123, pp. 179-185 (1959), the compounds exhibited antiagressive behaviorat doses of 1-25 mpk/i.p. Particularly suitable for this therapeutic-usecharacteristics are the 3 aza xanthene compounds and in particular10-dimethylaminopropylidene- 10 H[ 1 benzopyrano [2,3-c] pyridine.

Further, the compounds also exhibit marked antiserotonincharactertistics, said characteristic being common to those compoundsfound useful in the treatment and alleviation of migraine headaches. Ofparticular interest are those compounds of Formula I wherein Zrepresents N-methyl-piperidylidene and Q represents hydrogen. Ofparticular interest is the fact that this anti-serotonin activitymarkedly increases as the nitrogen atom of the aza xanthene nucleus ismoved from the 1- position to the 2- position, to the 3- position andfinally to the 4- position, (i.e. as depicted in structures V, IV, IIIand II, respectively). Thus, 5(N-methyl-4-piperidylidene)10H[1]benzopyrano[3,2-b] pyridine is anextremely potent antiserotonin agent.

The therapeutic compositions of matter described herein may beadministered parenterally, enterally or by inhalation techniques such asby the use of aerosols and other inhalation methods. Preferably, thecompounds are orally administered, oral administration being bestelfected by incorporating the compounds of this invention into dosageforms such as tablets, capsules, elixirs, solutions, suspensions, andthe like. Respective embodiments of the formulations containing thecompositions of this.

invention are as described below.

1 6 TABLET FORMULATION Formula: Mg./tablet 5 (N methyl 4 piperidylidene)5H- [1]-benzopyrano[2,3-b] pyridine maleate 100.00

Procedure.Mix together the 5-(N-methyl-4-piperidylidene) 5H[l]benzopyrano [2,3-b] pyridine maleate, citric acid, pluronic F-68, sodiumlauryl sulfate, lactose and dicalcium phosphate. Screen through No. 60mesh screen. Granulate the screened mix with an alcoholic solutioncontaining the polyvinylpyrrolidone. Carbowax 1500 and 6000. Addadditional alcohol, if necessary, to bring powder mix to a pasty mass.Add corn starch and continue mixing until uniform damp granules areformed. Pass the damp granulation through a No. 10 screen and dry in anoven at 100 C. for 12-14 hours. Screen the dried granulation using a No.16 screen, add sodium lauryl sulfate and magnesium stearate, mix andcompress on a tablet machine to specifications.

CAPSULE FORMULATION Formula: Mg./capsule 5 (N methyl 4 piperidylidene)5H[1]- benzopyrano [2,3-b1pyridine maleate 100.00 Citric acid 1.00Pluronic F-68 40.00 Sodium lauryl sulfate 20.00 Lactose 238.00

Magnesium stearate 1.00

Procedure.-Mix together the 5-(N-methyl-4-piperidylidene)5H[1]benzopyrano[2,3 b]pyridine maleate, citric acid, pluronic F-68,sodium lauryl sulfate and lactose. Pass through a No. screen. Add themagnesium stearate, mix and encapsulate into the proper size 2-piecegelatin capsule.

PARENTERAL FORMULATION Formula:

5 (N methyl 4 piperidylidene) 5H[1] benzopyrano [2,3-b1pyridine maleatemg./ 10-- 200.0 Benzyl alcohol, UF mg/l0 mL- 50.0 Methyl paraben, USP-mg./ 10 ml 18.0 Propyl paraben,USP mg./ 10 ml 2.0 Water ml 10 ELlXIRFORMULATION Formula: 5 (N methyl 4 piperidylidene)5H[1]benzopyrano[2,3-b]pyridine maleate gm./liter 10.0 Sodium citrate,USP ..ndo 10.0 Sodium benzoate, USP .1 do 1.0 Sorbitol solution, USP do200.0 Propylene glycol, USP do 50.0 Sucrose, food grade do 600.0Peppermint oil ml 0.1 Purified water, USP, q.s. to make liters 1.0

Procedure.Dissolve successively the sodium citrate, sodium benzoate, 5-(N-methyl-4-piperidylidene) -5H l] benzopyrano[2,3-b]pyridine maleate inapproximately 300-400 ml. of purified water with stirring and moderatewarming. Add the sorbitol solution, propylene glycol and sucrose andstir until homogeneous. Cool the mix to room temperature and add thepeppermint oil flavor. Add 5 gms. of a suitable filter and (Hi flowSuper-Cel-Johns- Manville) and filter the solution. Adjust the volume ofthe solution to 1. 'liter with additional purified water. Bottle theelixir in suitable sized containers. Each teaspoon ml.) of thisformation delivers 50 mg. of the active (bronchodilator) ingredient.

1. A compound having the structural formula:

x-N. v R': i W is a member "of the group consisting of H and OH, and Dis a member of the groupconsisting of piperidylidene, quinuclidylideneand R wherein R and R are members of the group consisting of hydrogenand lower alkyl and X and Y are respectively saturated lower aliphatichydrocarbyl and hydrocarbylidene radicals containing two to four carbonatoms.

2. A compound of claim 1 having the structural formula: '3"

and the pharmaceutically acceptable acid addition salts thereof, whereinQ is a member of the group consisting of hydrogen, lower alkyl, halogen,lower alkoxy and droxy, Z is a member of the group consisting of mula:

and

wherein R and R are members of the group consisting of hydrogen andlower alkyl and X and Y are respectively saturated lower aliphatichydrocarbyl and hydrocarbylidene radicals containing two to four carbonatoms.

3. A compound of claim 1 having the structural formula:

and the pharmaceutically acceptable acid addition salts thereof, whereinQ is a member of the group consisting of hydrogen, lower alkyl, halogen,lower alkoxy and hydroxy, Z is a member of the group consisting ofwherein A is a member of the group consisting of piperidyl, quinuclidyland W is a member of the group consisting of H and OH, and D is a memberof the group consisting of piperidylidene, quinuclidylidene and I 7 R1=Y-N 'wherein R and R are members of the group consisting of hydrogenand lower alkyl and X and Y are respectively saturated lower aliphatichydrocarbyl and hydrocarbyli- 'dene radicals containing two to fourcarbon atoms.

4. 'A compound of claim 1 having the structural forand thepharmaceutically acceptable acid addition salts wherein A is a member ofthe group consisting of pi peridyl, quinclidyl and amen-53 W is a memberof the group consisting of H and OH, and D is a member of the groupconsisting of piperidylidene, quinuclidylidene and v. R1, "1 =Y N I 7 t.R, wherein R and R are membersv of the group consisting of hydrogen andlower alkyl and X and Y are respectively saturated lower aliphatichydrocarbyl and hydrocarbylidene radicals containing two to four carbonatoms. f5. --A compound-of claim 1 having the structural formula:

:andt-the"pharmaceutically acceptable acid addition salts thereof,.wherein Q is a member of thegroup consisting ofthydrogen, lower'alkyl,--halogen, lower alkoxy and hydroxy, Z is a member of the groupconsisting "of and C=D wherein A a member of the group consisting ofpiperidyl, quinuclidyl and W is a member of the group consisting of Hand D is a member of the group consisting of piperidylidene,quinculidylidene and wherein R and R are members of the group consistingof hydrogen and lower alkyl and X and Y are respectively saturated loweraliphatic hydrocarbyl and hydrocanbylidene radicals containing two tofour carbon atoms.

6. A compound of claim 1 having the structuraliformula':

AAOH

and the pharmaceutically acceptable acid addition-salts thereof,--wherein 13, together with the carbon a'toms to which it is-attalched',represents a fused pyridinecringuQ is a member of the group consistingof hyrogen'," lower alkyl, lower alkoxy, halogen'and hydroxy, and A is amember of the group consisting of piperidyl quinuclidyl and :7; A lnpound of claim 1 havins -theii structural or ula:

if i D and the pharmaceutically acceptable acid addition salts thereof,wherein B, together with the carbon atoms to which it is attached,represents a fused pyridine ring, Q is a member of the group consistingof hydrogen, lower and thepharmaceutically acceptable acid additionsalts thereof,- wherein 8, together with-,the carbon atoms to whichitis'attached, represents a fused pyridine ring, Q. is a member of-thegroup consisting of hydrogen, lower alkyl, halogen, lower alkox andhydroxy, and A- is a member of the group consisting of piperidyl,quinuclidyl and 9. A compound of claim 7 having the sturcturalformula'r: .1

v or

and the pharmaceutically acceptable acid addition salts thereof, whereinQ is a member of the group consisting of hydrogen, lower alkyl, halogen,lower alkoxy and hydroxy, and D is a member of the group consisting ofpiperidylidene, quinuclidylidene and r -v l wherein R and R are membersof the group consisting of hydrogen and lower alkyl and Y is a saturatedlower ali- Phatiq-tihydrocarbylidene radical containing :two to :fourcarbonuatomsfnj t 7.. i .t

10. A compound o f claim, 1; having structural formula:

and the pharmaceutically acceptable acid addition salts thereof, whereinQ is a member of the group consisting of hydrogen, lower alkyl, halogen,lower alkoxy and bydroxy and D is a member of the group consisting ofpiperidylidene, quinuclidylidene and 1 1n s-. v. I V I, Q I .R, vwherein R and' R 'are members of the group consisting of hydrogen andlower alkyland Y is a saturated lower aliphatic hydrocarbylideneradicalcontaining two to four carbon atoms.

11. A compound of claim 1 having the structural formula:

and the pharmaceutically acceptable acid addition salts thereof, whereinQ is a member of the group consisting of hydrogen, lower alkyl, halogen,lower alkoxy and hydroxy and D is a member of the group consisting ofpiperidylidene, quinuclidplidene and /R1 =YN\ wherein R and R aremembers of the group consisting of hydrogen and lower alkyl and Y is asaturated lower aliphatic hydrocarbylidene radical containing two tofour carbon atoms.

12. A compound of claim 1 having the structural formula:

and the pharmaceutically acceptable acid addition salts thereof, whereinQ is a member of the group consisting of hydrogen, lower alkyl, halogen,lower alkoxy and hydroxy and D is a member of the group consisting ofpiperidylidene, quinuclidylidene and 17. A compound of claim 13 whereinthe benzopyrano tricyclic nucleus is a5I-I[1]benzopyrano[2,3-b]pyridine. 18. A compound of claim 14 whereinthe benzopyrano tricyclic nucleus is a 5H[l]benzopyrano[2,3-b]pyridine.19. A compound of claim 15 wherein the benzopyrano tricyclic nucleus isa 5H[1]benzopyrano[2,3-b1pyridine. 20. A compound of claim 16 whereinthe benzopyrano tricyclic nucleus is 5H[1]benzopyrano[2,3-b]pyridine.

21. A compound of claim 13 wherein the benzopyrano tricyclic nucleus is10H[1]benzopyrano[2,3-c]pyridine.

22. A compound of claim 7 wherein Q is hydrogen, said compound being5(dimethylaminopropylidene)5H[1]- benzopyrano [2,3-b] pyridine.

23. A compound of claim 7 wherein Q is hydrogen, said compound being5(dimethylaminopropylidene)5I-I[1]- benzopyrano [2,3-c] pyridine.

24. A compound of claim 7 wherein Q is hydrogen, said compound being10(dimethylaminopropylidene) 10H 1 -benzopyrano [3,2-b pyridine.

25. A compound of claim 7 wherein Q is hydrogen, said compound being10(dimethylaminopropylidene)10H [1 ]-benzopyrano [3 ,2-c] pyridine.

26. A compound of claim 7 wherein Q is hydrogen, said compound being5-(N-methyl-4-piperidylidene)-5I-I 1]-benzopyrano [2,3-b] pyridine.

27. A compound of claim 7 wherein Q is hydrogen, said compound being5-(N-methyl-4-piperidylidene)-5H [11-benzopyrano [2,3-c] pyridine.

28. A compound of claim 7 wherein Q is hydrogen, said compound being10-(N-methyl-4-piperidylidene)- 10H[l]-benzopyrano[3,2-b]pyridine.

29. A compound of claim 7 wherein Q is hydrogen, said compound being10-(N-methyl-4-piperidylidene)- 10H 1 benzopyrano [3 ,2-c] pyridine.

30. A compound of claim 19 wherein Q represents hydrogen, said compoundbeing 5-(3-quinuclidylidene) 5I-I[ l 1 benzopyrano [2,3-b1pyridine.

31. A compound of claim 20 wherein Q represents hydrogen, said compoundbeing 5 (dimethylaminoethylidene) 5H[ 1 benzopyrano [2,3-b pyridine.

32. A compound of claim 7 wherein D represents N-2,2,2-trifiuoroethyl-4-piperidylidene.

References Cited UNITED STATES PATENTS 5/1961 Judd et a1. 260293 9/1969Kaiser et a1. 260-293.4

US. Cl. X.R.

260-293.58, 294.9, R, 295 T, 296 H, 297 R, 297 T; 424-263, 267

